Association of Exposure to Phthalate Metabolites With Sex Hormones, Obesity, and Metabolic Syndrome in US Women

Key Points Question Is exposure to phthalate metabolites associated with levels of sex hormones and metabolic health in premenopausal and postmenopausal women? Findings In this cross-sectional study of 2004 US women, exposure to high levels of certain phthalate metabolites was significantly associated with low levels of sex hormone–binding globulin and metabolic health but not associated with total testosterone levels. Meaning Findings of this study suggest that there is a potential association of exposures to phthalates with reproductive and metabolic health according to menopausal status.

As per the National Cholesterol Education Program (NCEP)'s Adult Treatment Panel III, MS is the presence of three or more abnormal levels of cardiometabolic symptoms including glucose (FG) or hemoglobin A1c (HbA1c), waist circumference (WC), triglyceride (TG), high-density lipoprotein (HDL) cholesterol, and systolic and diastolic blood pressures (SBP and DBP). We defined MS using the NCEP criteria and considered MS if individuals were present with at least 3 symptoms of the following: FG level at least 100 mg/dL or HbA1c> 6 or taking diabetes medications, WC> 88 cm, TG> 150 mg/dL, HDL<50 mg/dL, and SBP ≥130 or DBP ≥85 or taking hypertension medications.

Statistical analysis:
We described the distribution of metabolite concentrations using centiles.
Mean with standard deviation (SD) or median with interquartile range (IQR) was used to describe continuous outcome data while categorical variables were summarized with proportions. Based on previous studies and clinical applications 22 , the primary analyses were carried out using categorized forms of metabolites whereas sensitivity analyses were performed on continuous forms of phthalate metabolites with continuous and categorized forms of sex hormones. The cutoffs were established for androgen markers according to age groups. Since most studies consider age 50-51 years as the reference category for menopause, women with age≥ 50 years were considered postmenopausal and women with age < 50 years were considered premenopausal.
Data-driven clustering among considered metabolites of phthalates and related standardized coefficients were used to create a composite score for each group. Furthermore, the grouping of phthalate metabolites was also done based on the molecular weight of metabolites or phthalate compounds. After obtaining grouping among metabolites and the composite exposure score for each group, the multivariable associations of log-transformed composite scores with TT, SHBG, obesity, and MS were examined using a survey weight-adjusted linear or Poisson regression analyses. The log transformation was made to improve the normality of continuous skewed phthalate metabolites and sex hormones data. The results were summarized using relative risk (RR) or regression coefficient (RC) along with a 95% confidence interval (CI) and p-value. In view of the analysis of multiple related outcomes, results from primary analysis were considered statistically significant at a 1% level of significance after adjusting for multiple comparisons.

eAppendix. Supplemental Results
In the adjusted analyses of combined phthalate metabolites, the composite score of group 4 was positively associated with TT concentrations among postmenopausal women whereas other HMW was inversely associated with TT concentrations among premenopausal women (eTable 5).